FDA Accepts First In Silico Drug Development Tool Under ISTAND Program to Help Predict Drug-Induced Liver Injury

FDA’s Center for Drug Evaluation and Research (CDER) has accepted the first Letter of Intent (LOI) for an in silico drug development tool (DDT) into the Innovative Science and Technology Approaches for New Drugs (ISTAND) DDT Qualification Program.

The DDT is an artificial intelligence (AI)-Driven Digital Liver Model for Prediction of Drug-Induced Liver Injury (DILI). It aligns with FDA's vision of optimizing drug development and evaluation while minimizing the use of animals in the nonclinical space, potentially expediting the availability of safe and effective treatments. As a New Approach Methodology (NAM), the DDT will work to improve predictive toxicology in humans, and aligns with CDER’s long-standing interest and investment in implementing the 3Rs (replacement, reduction, and refinement) of animal testing in drug development. It will help predict DILI by leveraging AI to compare the chemical structures of new drug candidates against historical reference drugs with known DILI risk. The model predictions will aim to complement other methods of DILI risk assessment as part of a weight-of-evidence approach.

“New technologies are showing incredible promise in helping improve and streamline drug development, with the ultimate goal of enhancing patient care,” said Michael Davis, MD, PhD, Acting Director of the CDER. “With this action, FDA is supporting innovative ways to optimize the development and evaluation of potential new therapies.”

The DDT will be used to assess DILI risk for small molecule new drug candidates. If qualified, this tool will complement existing preclinical data and support more informed decision-making before starting phase I clinical trials.

DILI is one of the most significant safety concerns in drug development and a leading cause of clinical trial termination and drug attrition during the Investigational New Drug process. Current modeling does not accurately identify risk of DILI in humans.

"The AI-Driven Digital Liver Model shows promise in assessing the risk of hepatotoxicity during preclinical phases of drug development," said Jeffrey Siegel, MD, Director of the Office of Drug Evaluation Sciences in CDER’s Office of New Drugs. “ISTAND’s efforts to advance novel approaches to drug development can help bring safe and effective therapies to patients faster.”

This LOI acceptance is the first step in a three-step DDT qualification process. In the next step, the company will submit a Qualification Plan. For the final step, the company will submit a full qualification package. Upon successful qualification, pharmaceutical company sponsors may use the qualified DDT in drug development programs within the specified context of use.

The ISTAND program supports the development of novel DDTs for use in regulatory applications for new medical products. ISTAND opens opportunities for DDTs that do not fit into established pathways for evaluation and application, such as for biomarkers and clinical outcome assessments.